Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.

Citation

Matthew E Bechard, Rana Smalling, Akimasa Hayashi, Yi Zhong, Anna E Word, Sydney L Campbell, Amanda V Tran, Vivian L Weiss, Christine Iacobuzio-Donahue, Kathryn E Wellen, Oliver G McDonald. Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis. Nature communications. 2020 Aug 13;11(1):4055

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PMID: 32792504

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